Apoptosis is a type of programmed cell death that regulates cellular physiology. Apoptosis can be activated by cell stresses, such as unfolded proteins. We have discovered a novel protein mediating mitochondrial outer membrane permeabilization in response to unfolded protein expression, using a small molecule screening approach. We screened 47,000 small molecules for those that could prevent polyglutamine- induced apoptosis in PC12 cells and identified three effective compounds. Using an affinity purification approach, we found that all four compounds act by inhibiting the same target. We found that upon expression of polyglutamine in PC12 cells, this target protein accumulates in mitochondria and activates the intrinsic apoptotic pathway by inducing mitochondrial outer membrane permeabilization (MOMP). We propose to define the mechanism by which these compounds inhibit the pro-apoptotic activity of this protein, and to determine how this protein induces MOMP, including identifying binding partners for this protein in the mitochondrial outer membrane. These studies may define a new apoptotic pathway. PUBLIC HEALTH RELEVANCE: Our goal is to define a new mechanism for inducing apoptosis in neurons. This mechanism may be involved in neurodegeneration. Small molecule inhibitors of this mechanism may eventually provide new therapeutic agents for neurodegenerative diseases.